Efficacy and safety of ezetimibe plus atorvastatin therapy

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1 Clinical Lipidology ISSN: (Print) (Online) Journal homepage: Efficacy and safety of ezetimibe plus atorvastatin therapy JoAnne M Foody, Peter P Toth, Andrew M Tershakovec, Thomas Musliner, Joanne E Tomassini, Robert S Lowe, David R Neff & Harry R Davis To cite this article: JoAnne M Foody, Peter P Toth, Andrew M Tershakovec, Thomas Musliner, Joanne E Tomassini, Robert S Lowe, David R Neff & Harry R Davis (214) Efficacy and safety of ezetimibe plus atorvastatin therapy, Clinical Lipidology, 9:4, To link to this article: Copyright 214 Future Medicine Ltd Published online: 18 Jan 217. Submit your article to this journal Article views: 1 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at

2 Clinical Lipidology Efficacy and safety of ezetimibe plus atorvastatin therapy Statin therapy is highly effective in reducing low-density lipoprotein cholesterol (LDL-C) and cardiovascular events; however, many high-risk patients on statin monotherapy do not achieve sufficient LDL-C lowering. Statin-dose uptitration, switching to more potent statins and/or addition of complementary lipid-lowering drugs has been recommended for these patients. Numerous clinical trials have shown that coadministration of statins with cholesterol absorption inhibitor, ezetimibe, improves LDL-C lowering and other lipid parameters more than statins alone, including doubling the statin dose. In clinical outcome trials, ezetimibe combined with simvastatin reduced ischemic events in high-risk patients with chronic kidney disease and aortic stenosis; the incremental benefit of LDL-C lowering when ezetimibe is added to statin therapy on cardiovascular risk reduction compared with statin monotherapy is currently being evaluated in an ongoing clinical trial. Recently, a fixed-dose combination of ezetimibe plus atorvastatin, a statin with greater potency than most other statins, was approved by the US FDA and offers a therapeutic option for high-risk patients who do not achieve recommended LDL-C levels on statin monotherapy. This article provides an update on the safety and efficacy of ezetimibe plus atorvastatin therapy. Keywords: atorvastatin ezetimibe fixed-dose combination therapy LDL-C lipids JoAnne M Foody *,1, Peter P Toth 2,3, Andrew M Tershakovec 4, Thomas Musliner 4, Joanne E Tomassini 4, Robert S Lowe 4, David R Neff 4 & Harry R Davis 4 1 Cardiovascular Wellness Program, Brigham and Women s Hospital, PB-136, Boston, MA 2115, USA 2 CGH Medical Center, Sterling, IL 6181, USA 3 University of Illinois College of Medicine, Peoria, IL 6165, USA 4 Merck Sharp & Dohme Corp., Whitehouse Station, NJ 8889, USA *Author for correspondence: Tel.: Fax: jfoody@partners.org Cholesterol-lowering management with statin therapy Substantial clinical trial evidence indicates that cardiovascular disease (CVD) risk reduction is related to the degree of lowdensity lipoprotein cholesterol (LDL-C) lowering achieved by therapeutic intervention [1 3].As such, LDL-cholesterol (LDL- C) reduction is the guideline-recommended treatment target for primary and secondary prevention of cardiovascular events [4 9]. Statin therapy has been shown to effectively reduce CVD risk in numerous clinical trials and is the first-line pharmacotherapy approach endorsed for lowering LDL-C [4 9]. National guidelines have recommended progressively lower LDL-C goals over time based on clinical trial evidence which has demonstrated that reducing LDL-C to very low concentrations is associated with greater CVD risk reduction [1,2]. Earlier guidelines developed by the US National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) included LDL-C <1 mg/dl as the optimal goal for primary prevention in persons with multiple coronary heart disease (CHD) risk factors and LDL-C <7 mg/dl as an optional goal for very high risk patients [1 13]. This latter target was also considered to be reasonable for high-risk patients with atherosclerotic vascular disease [14]. Other international guidelines similarly endorse these LDL-C target levels [4 9]. More intensive use of statin therapy and combination therapy has also been suggested, when appropriate, to achieve adequate LDL-C lowering in high-risk patients [4 9]. Levels of non-hdl-c and Apo B have also been recommended as secondary and alternate targets for therapy in patients with elevated triglycerides (TG; 2 mg/dl) by some guidelines [4,8 9,15]. For patients with cardio- part of /CLP Future Medicine Ltd Clin. Lipidol. (214) 9(4), ISSN

3 Foody, Toth, Tershakovec et al. metabolic risk, treatment to LDL-C <1 mg/dl, non- HDL-C <13 mg/dl and ApoB <9 mg/dl levels has been recommended for those individuals who are at high risk for CVD, and treatment to <7 mg/dl, <1 mg/dl and <8 mg/dl for LDL-C, non-hdl-c and ApoB, respectively are suggested for those who are at the highest risk [16].The recently published guideline from the American College of Cardiology and American Heart Association does not specify LDL-C targets per se, but rather focuses upon patient groups that are most likely to benefit from high-intensity (LDL-C lowering by 5%) and moderate-intensity statin (LDL-C lowered by 3 to <5%) in secondary and primary prevention of CVD risk [17]. Several clinical studies have shown the beneficial effects of statins on CVD risk reduction in both primary and secondary prevention studies (Figure 1) [18]. A large meta-analysis of 26 statin clinical trials demonstrated that standard statin therapy was associated with a 22% reduction (RR:.79; 95% CI:.76.8; p <.1) in the annual rate of major vascular events for each 1 mmol/l (38.6 mg/dl) reduction in LDL-C, and that studies of more intensive versus less intensive statin therapy in patients with baseline LDL-C levels in the range of mg/dl (down to average achieved LDL-C levels of mg/dl) resulted in further reductions in the incidence of cardiovascular events, consistent with the LDL reduction:risk reduction relationship observed at higher LDL-C levels [1]. In patients with lower CVD risk (5 to <1% risk), statin therapy also reduced CVD events by 21% (RR:.79; 95% CI:.77.81; p <.1) per 1 mmol/l reduction in LDL-C [19]. The clinical benefit of statin therapy outweighed the risk of adverse events in these patients, confirming the efficacy of statins in primary prevention. Intensive statin therapy has been shown to result in greater atherosclerotic disease regression than moderate therapy in intravascular ultrasound (IVUS) trials; however, these studies suggest that in many cases maximum statin therapy may not be sufficient and additional agents may be needed to optimize reduction of LDL-C and CVD risk [2]. Real world observational studies have also shown that many patients on statin monotherapy do not reach LDL-C levels set by some guidelines, particularly those with high CVD risk [3 38]. Despite substantial increases in the use of lipid-lowering therapy, and while attainment rates for LDL-C <1 mg/dl have improved from 18 to 67% during for high-risk CHD patients, only 3% of very-high-risk patients achieved LDL-C <7 mg/dl [38 43]. Similarly, although lipid treatment has improved over the years in patients with diabetes and metabolic syndrome, achievement of LDL-C goals in these patients is low (67% for LDL-C <1 mg/dl) and particularly those at very high risk (34% for LDL-C <7 mg/dl) [31]. This treatment gap has been attributed to various barriers including lack of optimal statin therapy, cost factors, compliance, tolerability and health provider n onadherence to current guidelines [3 31,37 38]. Several guidelines recommend statin uptitration, switching to more potent statins and/or statin combination therapy in these high-risk patients who do not reach sufficient LDL-C levels on statin therapy alone [4 9]. The American College of Cardiology/ American Heart Association guideline endorses that the maximum tolerated statin dose should be used in high-risk individuals for whom high- or moderateintensity statins have been recommended and that addition of a nonstatin cholesterol-lowering drug may be considered in those patients who have a lessthan-anticipated therapeutic response to statins if the risk-reduction benefit outweighs the safety risk, as well as those who do not tolerate the risk-appropriate intensity of statins or are statin intolerant [17]. Concern for potential side effects with higher statin doses and cost factors have limited the use of optimal statin therapy [4,41]. In addition, statin uptitration only provides an additional approximately 6% decrease in LDL-C level for each doubling of the dose [44], possibly related to counteracting factors such as increased intestinal cholesterol absorption and secretion of proprotein convertase subtilisin/kexin 9 (PCSK9). Studies have shown that high-potency statins are used less frequently than moderate potency lipid-lowering therapy in real-world clinical practice, attributed to patient noncompliance/intolerance, health provider nonadherence to current guidelines and/or cost factors [34,36,4,41,45]. In this regard, the availability of a generic formulation of atorvastatin, a class-leading statin that has greater LDL-C lowering efficacy than most other statins with proven benefit in reducing CVD, is becoming more commonly used [46]. While statins in combination with other lipidlowering agents having different mechanisms of action (e.g., niacin, fibrates, bile acid sequestrants and ezetimibe) can be used to provide further reductions in LDL-C, a lack of definitive evidence for greater CVD risk reduction with combination therapy compared with statin monotherapy alone has limited this approach [47 49]. In some clinical trials, both niacin and fibrates by themselves have been found to reduce CVD events, however, more recent studies of these agents, when combined with statins, have failed to demonstrate further reductions in CVD risk above statins alone [47,49]. Similarly, the bile acid sequestrant cholestyramine had a benefit on CVD events; however, to date there is no clinical outcome data that 442 Clin. Lipidol. (214) 9(4) future science group

4 Efficacy & safety of ezetimibe plus atorvastatin therapy Review 15 Treatment group Control group CARE HPS IDEAL PROSPER Events (%) 1 CARE IDEAL PROVE-IT HPS TNT PROSPER PROVE-IT WOSCOPS TNT WOSCOPS 5 ASCOT-LLA ASCOT-LLA AFCAPS AFCAPS LDL-C (mg/dl) Figure 1. Event rates versus low-density lipoprotein cholesterol lowering in statin monotherapy trials. Event rates plotted against low-density lipoprotein cholesterol level in primary (green) and secondary (red) prevention trials: AFCAPS [21]; ASCOT [22]; CARE [23]; HPS [24]; IDEAL [25]; PROSPER [26]; PROVE-IT [27]; TNT [28]; and WOSCOPS [29]. Events are defined as death by CHD or nonfatal myocardial infarction. Filled diamonds represent treatment groups and open circles control groups. To convert values for LDL-C to mmol/ml, multiply by LDL-C: LDL-cholesterol. Adapted with permission from [18]. compares the coadministration of bile acid s equestrant with statins versus statins alone [5]. Ezetimibe plus statin combination therapy has been shown to be effective and generally well tolerated for lowering LDL-C as well as improving other lipids in numerous clinical trials [51 54]. In clinical outcome trials, ezetimibe 1 mg plus simvastatin 2 mg produced significant reductions in major atherosclerotic events in patients with advanced CKD compared with placebo [55]. Additionally, ezetimibe 1 mg plus simvastatin 4 mg significantly reduced ischemic events in patients with low-to-moderate aortic stenosis, compared with placebo; the magnitude of the observed reduction in ischemic cardiovascular events in the two thirds of the population with less severe aortic stenosis was consistent with expectations for the degree of LDL-C lowering achieved [56,57]. However, these studies did not assess the specific contribution of ezetimibe on outcomes when added to statin therapy and the incremental benefit of ezetimibe when added to simvastatin compared with simvastatin monotherapy is being definitively addressed in an ongoing clinical outcomes trial [58,59]. In several studies, combination ezetimibe plus atorvastatin has been shown to be generally well tolerated and provides greater reductions in LDL-C and other lipids compared with doubling the atorvastatin dose when coadministered as separate tablets [6 63]. As such, a fixed-dose combination (FDC) of ezetimibe (1 mg) with atorvastatin (1, 2, 4 or 8 mg) was recently developed. The LDL-C lowering efficacy of the FDC has been demonstrated to be equivalent to coadministration of ezet- future science group 443

5 Foody, Toth, Tershakovec et al. imibe at the corresponding atorvastatin doses [64,65], and consistent with the broad clinical experience for coadministration of these two agents [66]. The FDC received US FDA approval in May 213 [66,67]. This review provides an update on the safety and efficacy of ezetimibe plus statin therapy, with an emphasis on its c ombination with atorvastatin. Statin therapy: mechanism of action, indications & safety profile Statins competitively inhibit 3-hydroxyl-3-methylgluaryl coenzyme A (HMG-CoA) reductase, resulting in reduced cholesterol biosynthesis in the liver and other peripheral organs, upregulation of hepatic cell surface LDL-C receptors and consequently removal of apolipoprotein B-containing lipoproteins (VLDL, IDL and LDL) from circulation [68]. Seven statins are currently approved for clinical use worldwide, including lovastatin (1987), simvastatin (1991), pravastatin (1991), fluvastatin (1993), atorvastatin (1996), pitavastatin (23) and rosuvastatin (23). All statins reduce LDL-C in a dose-dependent manner, and most can achieve LDL-C reductions of at least 2 3% [69]. Clinical outcome studies have demonstrated reductions in atherosclerotic cardiovascular events with lovastatin [21], simvastatin [7,71], pravastatin [23,26], atorvastatin [22,27 28] and rosuvastatin [72]. Fluvastatin has been shown to slow the progression of atherosclerosis and lower the risk of revascularization procedures for patients with CHD [73 75]. To date, the effect of pitavastatin on cardiovascular morbidity and mortality has not been determined. Differences in chemical structure and composition influence binding characteristics of statins to the active site of HMG-CoA reductase, and partially account for differences in statin potency [76]. Pharmacokinetic and pharmacodynamic properties also play a role in determining statin efficacy and safety [77]. Half-lives are generally between 1 and 3 h for all statins, except atorvastatin (14 h) and rosuvastatin (2 h). Lovastatin, simvastatin and atorvastatin are metabolized by CYP3A4, while fluvastatin, rosuvastatin and pitavastatin are metabolized primarily by CYP2C9. Pravastatin is not metabolized by CYP45 enzymes. Concurrent administration of statins with drugs that modify CYP activity may adversely affect statin efficacy, safety or tolerability [78]. Differences in statin pharmacokinetics may also favor some statins over others when used in special patient populations. Statins have been used in millions of patients for over 2 years and are generally safe and well tolerated. About 1 15% of patients in clinical practice, however, may report statin-related muscle symptoms which can contribute to discontinuation of treatment or reduced compliance [79,8]. This is becoming an increasingly important issue as guidelines continue to advocate for more aggressive lipid-lowering treatment targets [4 9,81]. Higher statin dose, low BMI, concomitant drug interactions, advanced age, liver or renal disease and susceptibility to muscle injury (alcohol consumption, drug interactions, heavy exercise and disease) are some of the factors associated with statin-induced myopathy [82 84]. Strategies for management of statin-associated muscle symptoms may help improve patients compliance and treatment efficacy [84 86]. Recent evidence has identified an association between statin therapy and a slightly higher risk of developing diabetes mellitus [72]. Meta-analysis of randomized placebo-controlled statin trials found a significant but low risk for development of diabetes during approximately 4 years of treatment (OR: 1.9; 95% CI: ) [87]. More intensive statin treatment may also be associated with increased risk when compared with lower statin doses (OR: 1.12; 95% CI: ) [88]. These findings led the FDA to issue a safety label change for all statins, warning of increased blood sugar and glycosylated hemoglobin levels; however, the risk was said to be small and greatly outweighed by the benefit, and therefore should not affect the use of statins in appropriate patients [89]. In primary prevention studies of lowerrisk patients, the reduction of CVD risk and mortality also outweighed the diabetes risk, including highdose statin therapy [9,91]. Moreover, the increased risk of diabetes was greater in those patients predisposed to diabetes, as predicted by baseline factors including higher fasting serum glucose levels (95 to <126 mg/ dl), HbA1c (>6%), obesity (>3 kg/m 2 ), higher triglyceride levels (>15 mg/dl) and a history of hypertension or metabolic syndrome [91,92]. These findings reaffirm the value of statin therapy in reducing CVD risk; however, the associated benefit and risk should be carefully assessed for each patient. Efficacy & safety of atorvastatin therapy Atorvastatin is one of the most widely prescribed statins in the world [93]. Daily administration of atorvastatin 1, 2, 4 or 8 mg is highly effective in lowering LDL-C levels, with dose-dependent mean reductions of approximately 37 53% [94]. Atorvastatin is metabolized by CYP3A4 and 3A5 to ortho-hydroxy atorvastatin and para-hydroxy atorvastatin, which extends the half-life for inhibiting HMGCoA reductase to 2 3 h, and contributes to a higher potency when compared with most other statins [95,96]. Concomitant use of drugs that inhibit CYP3A4 may increase serum plasma concentrations of atorvastatin and the risk of 444 Clin. Lipidol. (214) 9(4) future science group

6 Efficacy & safety of ezetimibe plus atorvastatin therapy Review myotoxicity. As with most statins, atorvastatin undergoes extensive first pass metabolism in the liver and is eliminated primarily in bile. Hepatic dysfunction is therefore a risk factor for statin-induced myopathy. Compared with other statins, atorvastatin and fluvastatin are minimally excreted in the urine and therefore may have better safety profiles in patients with renal dysfunction [97 99]. Atherosclerosis is a progressive disease that starts early in life, and is the underlying cause of CVD. Several surrogate markers have been used to evaluate the effect of atorvastatin on atherosclerotic progression. In the 2-year ASAP trial comparing aggressive versus conventional care in high-risk patients with heterozygous familial hypercholesterolemia (HeFH), atorvastatin 8 mg was associated with a significant decrease in mean carotid intimal-media thickness (cimt), while cimt significantly increased with simvastatin 4 mg (-.31 mm vs +.36 mm) [1]. After an additional 2 years, no further decrease in cimt was observed in patients continuing on atorvastatin 8 mg while significant reductions were seen in those switching from simvastatin 4 mg to atorvastatin 8 mg (baseline:.95 mm; study end:.92; p =.1) [11]. In the ARBITER trial which studied patients meeting NCEP ATP II criteria for pharmacologic lipid-lowering therapy (46% with known cardiovascular disease), atorvastatin 8 mg significantly decreased cimt versus no change with pravastatin 4 mg/day [12]. The effects of maximal dose atorvastatin (8 mg) and rosuvastatin (4 mg) on coronary atherosclerosis were evaluated in the SATURN trial using IVUS in patients with coronary stenosis. In this study, significant regression of coronary atherosclerosis as measured by percent atheroma volume was observed for both treatments (.99% for atorvastatin, 1.22% for rosuvastatin) [2]. Atorvastatin has been evaluated in numerous clinical outcome trials and shown to be effective in primary and secondary prevention of cardiovascular events. The ASCOTT-LAA trial studied patients at moderate risk with hypertension and 3 CHD risk factors but without CHD, and demonstrated that atorvastatin 1 mg reduced the composite end point of nonfatal MI and fatal CHD by 36% after a median of 3.3 years when compared with placebo [22]. Diabetes is a major risk factor for CHD and the ADA recommends statin therapy for all diabetic patients without CVD who are over age 4 with one or more additional cardiac risk factors [13]. This recommendation is supported by the 3.9-year randomized placebo-controlled CARDS trial of atorvastatin 1 mg in 2838 diabetic patients with no evidence of CHD, where atorvastatin reduced the primary end point of acute CHD events, coronary revascularization, or stroke by 37% [14]. In the PROVE IT (TIMI 22) trial of high-risk patients hospitalized with acute coronary syndrome, starting treatment with atorvastatin 8 mg produced a significant 16% relative reduction in death or major cardiovascular events compared with pravastatin 4 mg at completion of the month study [27]. In a second acute coronary syndrome (ACS) study (MIRACL), initiation of atorvastatin 8 mg therapy h after an ACS significantly reduced recurrent symptomatic myocardial ischemic events within the first 16 weeks of treatment [15]. The TNT study evaluated patients with stable nonacute CHD and slightly elevated LDL-C levels who were treated with atorvastatin 1 mg to lower LDL-C to approximately 1 mg/dl or with atorvastatin 8 mg to reach an LDL-C target of approximately 75 mg/ dl. In this trial, atorvastatin 8 mg produced a 22% relative reduction in the first occurrence of a major cardiovascular event (death from CHD, nonfatal nonprocedure-related MI, resuscitation after cardiac arrest or fatal or nonfatal stroke) when compared with atorvastatin 1 mg [28]. In ALLIANCE, an open-label study in 2442 CHD patients compared treatment with atorvastatin titrated to reach an LDL-C target of <8 mg/dl versus usual care in reducing cardiovascular events (cardiac death, nonfatal MI, resuscitated cardiac arrest, revascularization or unstable angina requiring hospitalization) [16]. After an average of 51 months treatment, more intensive treatment resulted in significantly greater reductions in LDL-C (-34.5% vs -23.3%), significantly higher percentage achievement of NCEP ATP III targets (72.4% vs 4.%), and significantly fewer cardiovascular events (23.7% vs 27.7%; relative risk reduction of 17.1%) compared with usual care. Atorvastatin has also been shown to significantly reduce the incidence of stroke in patients with hypertension (ASCOT-LAA [22]) or in patients experiencing prior cerebrovascular events (SPARCL) [17]. A post hoc analysis of the SPARCL study showed a higher incidence of hemorrhagic stroke in patients without CHD who had experienced a stroke or transient ischemic attack within 6 months prior to receiving atorvastatin 8 mg vs placebo, and this is noted as a precaution for use in patients with recent stroke or transient ischemic attack in the prescribing i nformation [46,18]. While the majority of clinical trials have demonstrated statistically significant improvements in cardiovascular outcomes with atorvastatin, it should be noted that other trials have not, including ASPEN and IDEAL. The ASPEN trial evaluated atorvastatin 1 mg versus placebo in 241 patients with type 2 diabetes, and after a median follow-up of 4 years, no future science group 445

7 Foody, Toth, Tershakovec et al. statistical difference between the two treatments was observed for the primary composite end point (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, recanalization, coronary artery bypass surgery, resuscitated cardiac arrest and worsening or unstable angina requiring hospitalization) [19]. The ASPEN study group suggested that these results may have been related to the overall study design, patient population, the nature of the primary end point as well as required protocol changes due to changes in ATP III treatment guidelines that affected enrollment, and emphasized the continued importance of LDL-C lowering treatment for diabetic patients. In the IDEAL study of 8888 patients with a history of acute MI, comparison of high-dose atorvastatin 8 mg versus usual-dose simvastatin 2 mg showed no significant difference in the reduction of the primary end point of major coronary events after a median follow-up of 4.8 years [25]. Atorvastatin did provide significant improvements over simvastatin in other secondary end points and nonfatal acute MI, suggesting the benefit of intensive lowering of LDL-C in this patient population. Atorvastatin has a favorable safety and tolerability profile in a wide variety of patients, including the elderly [11,111], patients with Type 2 diabetes mellitus [14,19,112], ACS [27], CHD [28] and chronic kidney disease [113]. Cases of rhabdomyolysis with acute renal failure are rare, and persistent elevations in serum transaminases have been reported, particularly at higher doses [46, ]. As already noted, statins, including atorvastatin, are associated with a slight increase in risk of new-onset Type 2 diabetes mellitus [87]. In one study of primary care patients with hypercholesterolemia, atorvastatin 1 8 mg was associated with a significant increase in plasma insulin (25 45%) and glycated hemoglobin (HbA1c) levels (2 5%) and decreased insulin sensitivity after 2 months of therapy, when compared with either baseline levels or placebo [116]. Recent meta-analyses suggest that different types and doses of statins may have the potential for increasing the incidence of diabetes mellitus [117]. Comparison of lower dose statin therapy versus atorvastatin 8 mg in over 15, patients with CHD but without diabetes mellitus showed an increased risk of new-onset diabetes with atorvastatin 8 mg when two or more new-onset diabetes risk factors were present (fasting blood glucose >1 mg/dl, fasting triglycerides >15 mg/dl, body mass index >3 kg/m 2 and history of hypertension); however, reductions in cardiovascular events were also significantly greater with more intensive therapy [118]. The FDA issued a statement r egarding the risks a ssociated with statin use [119]. Ezetimibe overview Ezetimibe selectively inhibits the absorption of dietary and biliary cholesterol (and related phytosterols) in the small intestine by blocking the activity of the Niemann-Pick C1 Like 1 (NPC1L1) sterol transport protein [12,121]. The inhibition of NPC1L1 by ezetimibe subsequently reduces the incorporation of cholesterol into chylomicrons. The decline in chylomicron cholesterol results in a decreased delivery of cholesterol to the liver that leads to a compensatory upregulation of hepatic LDL receptors and increased plasma clearance of atherogenic ApoB-containing lipoproteins. Through its interaction with the hepatic NPC1L1 transporter, ezetimibe can also increase cholesterol reabsorption from bile, thereby reducing the hepatic pool of cholesterol and further augmenting LDL-C clearance [122]. When coadministered with a statin, the combined inhibition of cholesterol absorption by ezetimibe and cholesterol synthesis by a statin substantially reduces LDL-C through a final common pathway of enhanced upregulation of LDL receptors and clearance of lipoproteins from the plasma [52 53,121,123]. Ezetimibe specificity for NPC1L1 is well established, and no effects on the absorption of triglycerides, ethinyl estradiol, progesterone, fat-soluble vitamins or bile acids have been observed. In vitro assays evaluating all known lipid pathways found that ezetimibe and its glucuronide did not inhibit any known biochemical or cellular processes, including ACAT, to a degree that could be clinically relevant [124,125]. Ezetimibe also does not block pancreatic lipase as seen with orlistat, or sequester bile acids or block their absorption as with bile acid sequestrants (resins). Over 1 toxicology studies were used to assess the preclinical safety of ezetimibe, and no target organ toxicity was seen in any study [126]. These results are consistent with the clinical safety profile of ezetimibe [127]. Clinical studies evaluating the lipid-altering efficacy of ezetimibe Ezetimibe has been approved for use as monotherapy or in combination with statins for patients with primary (heterozygous familial and nonfamilial) hyperlipidemia for the reduction of elevated levels of total cholesterol, LDL-C, ApoB and non-hdl-c, or as monotherapy for patients with homozygous familial sitosterolemia in reducing elevated levels of camepsterol and sitosterol [127]. It is also approved for use in combination with statins for treatment of homozygous familial hypercholesterolemia and in combination with fenofibrate for treatment of adult patients with mixed hyperlipidemia [127]. Ezetimibe monotherapy has been extensively evaluated in adults with 446 Clin. Lipidol. 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8 Efficacy & safety of ezetimibe plus atorvastatin therapy Review primary hypercholesterolemia and shown to produce significant reductions in LDL-C of approximately 19% with concomitant improvements in other key lipid parameters [123,128]. Ezetimibe monotherapy resulted in LDL-C reductions of 7 26% in statinintolerant patients with perceived adverse effects on statin therapy, including high-dose statins [ ]. Co-administration of ezetimibe with statins has been shown to inhibit cholesterol absorption as well as synthesis, resulting in significantly larger reductions in LDL-C and greater achievement of guideline-recommended LDL-C targets than with statin monotherapy [ ] or statin doubling [6 63, ]. These improvements have been demonstrated in a number of high-risk patient populations [52], including patients with homozygous (Ho) or heterozygous (He) familial hypercholesterolemia (FH) [131, ], diabetes mellitus [ ], metabolic syndrome [ ], nonalcoholic fatty liver disease [15], chronic kidney disease [151,152], CHD [62,138,153] and aortic stenosis [56] as well as in statin-intolerant patients [ ,154]. Lipid-altering efficacy & safety of ezetimibe plus atorvastatin in clinical studies Several studies have evaluated the complementary effects of blocking cholesterol synthesis with atorvastatin and inhibition of cholesterol absorption with ezetimibe in a variety of patient populations (Table 1). In a randomized placebo-controlled factorial trial of 628 statin-naïve hypercholesterolemic patients with LDL-C levels between 145 and 25 mg/dl and triglycerides 35 mg/dl, evaluation of pooled data for coadministration of ezetimibe 1 mg and atorvastatin (1, 2, 4 or 8 mg) showed an additional 12% reduction in LDL-C compared with atorvastatin monotherapy [132]. LDL-C reductions for individual treatment groups ranged from -5 to -6% for coadministration versus -35 to -5% for atorvastatin alone. Ezetimibe combined with the lowest available dose of atorvastatin (1 mg) produced a mean LDL-C reduction comparable to that of atorvastatin 8 mg, the highest prescribed dose. Three randomized, double-blind, placebo-controlled trials have evaluated ezetimibe added to ongoing atorvastatin therapy in patients with primary hypercholesterolemia who had not achieved NCEP ATP treatment targets with statin alone [155,156], or in patients with established CHD and LDL-C levels >1 mg/dl with atorvastatin 1 or 2 mg [157]. In these studies, ezetimibe added-on to ongoing atorvastatin therapy produced significantly greater reductions in levels of LDL-C (2 27%), as well as total cholesterol, non-hdl-c, Apo B, triglycerides and C-reactive protein (when measured), and increases in HDL-C levels compared with placebo. Addition of ezetimibe to statin monotherapy significantly improved attainment of LDL-C goals. Four randomized double-blind clinical trials were designed to compare the addition of ezetimibe to ongoing atorvastatin versus doubling the atorvastatin dose in patients with moderate CHD risk, high CHD risk with or without clinically diagnosed cardiovascular disease and a high-risk elderly population [6,62 63,138]. In all studies, ezetimibe added to ongoing atorvastatin provided an additional LDL-C reduction of 14 2% compared with atorvastatin titration to the next higher dose, resulting in significantly greater achievement of LDL-C targets and significantly greater reductions in other key lipid parameters. A fifth study in homozygous familial hypercholesterolemia patients evaluated the efficacy of adding ezetimibe to ongoing atorvastatin 4 mg or simvastatin 4 mg (allowing for LDL apheresis if it was part of the patients therapeutic regimen) [141]. For patients with LDL-C levels above 1 mg/dl after 4 weeks of treatment, the statin dose was increased to 8 mg. At the end of 12 weeks, coadministration of ezetimibe with statin (4 or 8 mg) reduced LDL-C significantly more than statin 8 mg therapy (-2.7% vs -6.7%; p =.7) in this very high-risk patient population. Use of ezetimibe alone or in combination with atorvastatin 1 mg was evaluated in high-risk, statinintolerant patients with coronary artery disease or equivalent (data not shown in Table 1) [129]. Ezetimibe monotherapy was well tolerated and produced a significant mean reduction in LDL-C of 2%; however, only 9% of patients achieved their LDL-C target. Subsequent addition of atorvastatin 1 mg twice a week to ezetimibe 1 mg/day was also tolerated by these patients, and combined therapy provided a 37% reduction in LDL-C compared with baseline values, and an 84% achievement of LDL-C goals. A recent study used a novel treat-to-target design to compare the LDL-C lowering efficacy of sequential treatment options in high cardiovascular risk patients with primary hypercholesterolemia [61]. After a 5-week run-in on atorvastatin 1 mg/day, subjects who were not at the LDL-C treatment target of <1 mg/dl were randomized to three groups; addition of ezetimibe to stable atorvastatin 1 mg, doubling atorvastatin to 2 mg or switching to rosuvastatin 1 mg, a more potent statin. After 6 weeks (Period I), coadministration of ezetimibe with atorvastatin 1 mg reduced LDL-C significantly more than atorvastatin 2 mg or rosuvastatin 1 mg (22.2% vs 9.5% or 13%, respectively; p <.1). Patients with LDL-C levels 1 mg after receiving atorvastatin 2 mg during future science group 447

9 Foody, Toth, Tershakovec et al. Table 1. Clinical studies evaluating the lipid-lowering efficacy of ezetimibe plus atorvastatin. Study (year) Study number Trial design Inclusion criteria (mg/dl) Population Therapy (mg/day) Patients (n) Study length (weeks) First-line studies: eze plus statins coadministered in statin-naive patients LDL-C TG LDL-C Non- HDL-C Treatment difference (% change from baseline) Ref. HDL-C Total C TG Apo B hscrp Ballantyne et al. (23) o HC A1, A2, A4, A8 A1, A2, A4, A8 + E * -11.2* 3.* 9.* -8.3* -9.3* -1.* [132] Second-line studies: eze added to ongoing statin therapy vs placebo Gagne et al. (22) Pearson et al. (25) Cruz- Fernandez et al. (25) o HC Ongoing statin + Pbo Ongoing statin + E1 4 1 o HC Ongoing statin + Pbo Ongoing statin + E Established CHD Ongoing A1/2 + Pbo Ongoing A1/2 + E Above ATP III target 8 Above ATP III target 21.3*** 19.9*** 1.7** -14.7*** -11.1*** -15.5*** -9.7** [155] *** -2.6*** 2.1*** ND -11.2*** -16.3*** -1.1** [156] *** -24.6*** 2.8** -17.7*** -14.6*** -2.7*** ND [157] Second-line studies: eze added to ongoing statin therapy vs doubling or switching Gagne et al. (22) 18 HoFH ± LDL apheresis A4 or S4 A8 or S8 A4 or S4 A4 or S4 + E1 A8 or S8 + E ** ND *** # ND [141] Studies 692, 2173/2246, 4, 83/84, 3, 79, 9, 112 were included in a pooled analyses of 27 studies [54,188]. Treatment difference: percentage change with statin plus ezetimibe 1 mg minus percentage change with statin plus placebo, statin doubling, or statin switch. Ongoing statins: atorvastatin (1, 2, 4, 8 mg), cerivastatin (.2,.3,.4,.8 mg), fluvastatin (2, 4, 8 mg), lovastatin (1, 2, 4 mg), pravastatin (1, 2, 4 mg), simvastatin (1, 2, 4, 8 mg). Atorvastatin (1 8 mg) + ezetimibe 1 mg (n = 152) reduced LDL-C by 25%; atorvastatin (1 8 mg) + placebo (n =136) reduced LDL-C by 4.%. Ongoing statins: atorvastatin (1, 2, 4, 8 mg); fluvastatin (1, 2, 4, 8 mg; one patient took 16 mg); lovastatin (1, 2, 4, 8 mg); pravastatin (1, 2, 4, 8 mg); simvastatin (1, 2, 4, 8 mg). Atorvastatin (1 8 mg) + ezetimibe 1 mg (n = 769) reduced LDL-C by 25 28%; atorvastatin (1 8 mg) + placebo (n = 389) reduced LDL-C by 3 5%. Statin dose titrated during study. Only used data from indicated week. # Calculated median percentage change due to wide intrapatient variability in the effects on mean apo B values. p <.5; p <.1; p <.1. A: Atorvastatin; ATP: Adult treatment panel; CHD: Coronary heart disease; E: Ezetimibe; eze: Ezetimibe; HC: Hypercholesterolemia; HDL-C: HDL-cholesterol; HeFH: Heterozygous familial hypercholesterolemia; HoFH: Homozygous familial hypercholesterolemia; LDL-C: LDL-cholesterol; ND: Not determined; Pbo: Placebo; R: Rosuvastatin; S: Simvastatin; TG: Triglycerides. 448 Clin. Lipidol. (214) 9(4) future science group

10 Efficacy & safety of ezetimibe plus atorvastatin therapy Review Table 1. Clinical studies evaluating the lipid-lowering efficacy of ezetimibe plus atorvastatin (cont.). Study (year) Study number Trial design Inclusion criteria (mg/dl) Population Therapy (mg/day) Patients (n) Study length (weeks) Second-line studies: eze added to ongoing statin therapy vs doubling or switching (cont.) LDL-C TG LDL-C Non- HDL-C Treatment difference (% change from baseline) Ref. HDL-C Total C TG Apo B hscrp Stein et al. (24) % HeFH, 3 32% CHD 37 39%; 2 CV risk factors A1 run-in A1 + E1 A1 run-in A1 + A > * -14.2* * -5.4* ND [138] Conard et al (28) 79 Moderate CHD risk A2 run-in A2 + E1 A2 run-in A *** -16*** 2-12*** -9-14*** 2 [6] Leiter et al (28) 9 High CHD risk A4 run-in A4 + E1 A4 run-in A *** -1*** -7*** -1*** -7 [62] Zieve et al (21) 112 High CHD risk; 65 years A1 run-in A1 + E1 A1 run-in A /> *** -12*** 2* -8*** -6*** -9*** -3 [63] Bays et al. (213) 139 High CHD risk A1 run-in A1 + E1 A1 run-in A2 A1 run-in R *** -9.1*** -1.1*** -7.6*** *** -5.8*** *** -4.3*** [61] Above ATP III Target on A2 A2 + E1 Above ATP III Target on A2 A *** -9.3*** *** Studies 692, 2173/2246, 4, 83/84, 3, 79, 9, 112 were included in a pooled analyses of 27 studies [54,188]. Treatment difference: percentage change with statin plus ezetimibe 1 mg minus percentage change with statin plus placebo, statin doubling, or statin switch. Ongoing statins: atorvastatin (1, 2, 4, 8 mg), cerivastatin (.2,.3,.4,.8 mg), fluvastatin (2, 4, 8 mg), lovastatin (1, 2, 4 mg), pravastatin (1, 2, 4 mg), simvastatin (1, 2, 4, 8 mg). Atorvastatin (1 8 mg) + ezetimibe 1 mg (n = 152) reduced LDL-C by 25%; atorvastatin (1 8 mg) + placebo (n =136) reduced LDL-C by 4.%. Ongoing statins: atorvastatin (1, 2, 4, 8 mg); fluvastatin (1, 2, 4, 8 mg; one patient took 16 mg); lovastatin (1, 2, 4, 8 mg); pravastatin (1, 2, 4, 8 mg); simvastatin (1, 2, 4, 8 mg). Atorvastatin (1 8 mg) + ezetimibe 1 mg (n = 769) reduced LDL-C by 25 28%; atorvastatin (1 8 mg) + placebo (n = 389) reduced LDL-C by 3 5%. Statin dose titrated during study. Only used data from indicated week. # Calculated median percentage change due to wide intrapatient variability in the effects on mean apo B values. p <.5; p <.1; p <.1. A: Atorvastatin; ATP: Adult treatment panel; CHD: Coronary heart disease; E: Ezetimibe; eze: Ezetimibe; HC: Hypercholesterolemia; HDL-C: HDL-cholesterol; HeFH: Heterozygous familial hypercholesterolemia; HoFH: Homozygous familial hypercholesterolemia; LDL-C: LDL-cholesterol; ND: Not determined; Pbo: Placebo; R: Rosuvastatin; S: Simvastatin; TG: Triglycerides. future science group 449

11 Foody, Toth, Tershakovec et al. Table 1. Clinical studies evaluating the lipid-lowering efficacy of ezetimibe plus atorvastatin (cont.). Study (year) Study number Trial design Inclusion criteria (mg/dl) Population Therapy (mg/day) Patients (n) Study length (weeks) Second-line studies: eze added to ongoing statin therapy vs doubling or switching (cont.) LDL-C TG LDL-C Non- HDL-C Treatment difference (% change from baseline) Ref. HDL-C Total C TG Apo B hscrp Bays et al. (213) (cont.) Above ATP III Target on R1 A2 + E1 Above ATP III Target on R1 R *** -9.8*** *** -7.1* -7.7*** Studies 692, 2173/2246, 4, 83/84, 3, 79, 9, 112 were included in a pooled analyses of 27 studies [54,188]. Treatment difference: percentage change with statin plus ezetimibe 1 mg minus percentage change with statin plus placebo, statin doubling, or statin switch. Ongoing statins: atorvastatin (1, 2, 4, 8 mg), cerivastatin (.2,.3,.4,.8 mg), fluvastatin (2, 4, 8 mg), lovastatin (1, 2, 4 mg), pravastatin (1, 2, 4 mg), simvastatin (1, 2, 4, 8 mg). Atorvastatin (1 8 mg) + ezetimibe 1 mg (n = 152) reduced LDL-C by 25%; atorvastatin (1 8 mg) + placebo (n =136) reduced LDL-C by 4.%. Ongoing statins: atorvastatin (1, 2, 4, 8 mg); fluvastatin (1, 2, 4, 8 mg; one patient took 16 mg); lovastatin (1, 2, 4, 8 mg); pravastatin (1, 2, 4, 8 mg); simvastatin (1, 2, 4, 8 mg). Atorvastatin (1 8 mg) + ezetimibe 1 mg (n = 769) reduced LDL-C by 25 28%; atorvastatin (1 8 mg) + placebo (n = 389) reduced LDL-C by 3 5%. Statin dose titrated during study. Only used data from indicated week. # Calculated median percentage change due to wide intrapatient variability in the effects on mean apo B values. p <.5; p <.1; p <.1. A: Atorvastatin; ATP: Adult treatment panel; CHD: Coronary heart disease; E: Ezetimibe; eze: Ezetimibe; HC: Hypercholesterolemia; HDL-C: HDL-cholesterol; HeFH: Heterozygous familial hypercholesterolemia; HoFH: Homozygous familial hypercholesterolemia; LDL-C: LDL-cholesterol; ND: Not determined; Pbo: Placebo; R: Rosuvastatin; S: Simvastatin; TG: Triglycerides. 45 Clin. Lipidol. (214) 9(4) future science group

12 Efficacy & safety of ezetimibe plus atorvastatin therapy Review Period I were randomized to addition of ezetimibe to atorvastatin 2 mg or titration of atorvastatin a second time from 2 to 4 mg. After 6 weeks, reduction of LDL-C was significantly greater with combination therapy (-17.4% vs 7.5%; p <.1). Patients with LDL-C levels 1 mg after 6 weeks of rosuvastatin 1 mg treatment during Period 1 were switched to ezetitimbe plus atorvastatin 2 mg or had rosuvastatin 1 mg doubled to 2 mg. For these patients, combination therapy produced significantly greater reductions in LDL-C than rosuvastatin 2 mg (-17.1% vs 7.5%; p <.1). Relative to comparative treatments with atorvastatin or rosuvastatin monotherapy, ezetimibe added to atorvastatin resulted in significantly greater attainment of LDL-C targets <1 or <7 mg/dl (Figure 2), and significantly greater reductions in total cholesterol, non-hdl-c and Apo B (significant for all but one comparison). The broad clinical experience demonstrating the lipid-lowering efficacy and tolerability of coadministered ezetimibe plus atorvastatin led to the development of an FDC of ezetimibe/atorvastatin that recently received FDA approval [66,67]. The FDC meets criteria for clinical equivalence to coadministration of the separate components [64,65]. The availability of ezetimibe/atorvastatin fixed-dose tablets provides a convenient, efficacious and well-tolerated LDL-C-lowering therapy option for patients who do not achieve guideline-recommended LDL-C levels on statin monotherapy. Use of a single tablet regimen ezetimibe/atorvastatin may also help to improve compliance in the combined use of these two agents as has been shown for other single-pill combination therapies [ ]. Ezetimibe plus statin therapy in surrogate & clinical outcome trials While a vast amount of evidence exists demonstrating reductions in clinical cardiovascular events with statins, the data for ezetimibe added to statins is much more limited. For this reason, these data will be summarized below. Ezetimibe plus statin combination therapy has been assessed in one surrogate imaging (cimt) trial in patients with HeFH [142], two completed cardiovascular outcome trials (one in patients with CKD and another in patients with aortic stenosis) [56,151] and in an additional cardiovascular outcome trial study in acute coronary syndrome patients that is currently ongoing [58]. These trials are summarized below and in Table 2. While all of these studies assessed ezetimibe in combination with simvastatin, it is assumed that the results can be extrapolated to ezetimibe combined with other statins (including atorvastatin) that produce similar LDL-C reductions, in light of existing evidence that the relationship between clinical outcomes and statin therapy is primarily related to the absolute LDL-C achieved [1 2,19]. ENHANCE In the ENHANCE trial, the effect of ezetimibe added to simvastatin 8 mg on the CVD surrogate end point of cimt was compared with the effect of adding placebo in 72 patients with HeFH [142]. Although coadministration of ezetimibe reduced LDL-C levels significantly more (16.5%) than simvastatin 8 mg (p <.1), the mean changes in cimt (.111 ±.38 mm vs.58 ±.37 mm, respectively; p =.29), were similar after 2 years, with neither treatment producing a significant reduction in cimt. The authors of the study concluded that this neutral effect was likely due to long-term prior statin treatment in the majority of patients and low-baseline cimt levels (essentially falling within the normal range) as evidenced in other trials where up to 8 mg of atorvastatin provided no reduction in cimt in patients on prior statin therapy or with low-baseline cimt [11, ]. This premise was further supported by findings in the SANDS and VYCTOR studies, wherein patients had higher baseline mean cimt levels (.8.81 mm and mm, respectively) than in ENHANCE ( mm), and ezetimibe plus statin and statin therapies produced comparable reductions in cimt progression in proportion to the magnitude of LDL-C lowering [ ]. Based on the ENHANCE results, some had recommended that other combination statin therapies including fibrates, niacin and bile acid sequestrants should be used before ezetimibe, until results from the ongoing ezetimibe outcomes trial are available [58,59]; however, it should be noted that reductions in CVD events with these agents on top of statins have not been demonstrated in randomized, controlled clinical trials [47 49]. Other expert groups have supported the continued use of ezetimibe, recognizing the limitations of cimt as a surrogate measure in assessing therapeutic interventions in some settings, consistent with a meta-analysis showing that the reduction of cimt progression and CVD events was not related [169,17]. SHARP The recently reported SHARP trial compared combination ezetimibe/simvastatin 1/2 mg with placebo in 927 patients with moderate-to-advanced CKD, including 323 patients on dialysis and 6247 who were not on dialysis. [55,151] The combination reduced major atherosclerotic events (MAE), including nonfatal myocardial infarction or coronary death, nonhemorrhagic stroke or any arterial revascularization future science group 451

13 Foody, Toth, Tershakovec et al. A 1 LDL-C <1 mg/dl LDL-C <7 mg/dl % patients attaining specified LDL-C target LDL-C 1 to 16 mg/dl on: Treatment period I A1 E1 + A2 (n = 119) A1 A2 (n = 471) A1 R2 (n = 915) A1 E1 + A1 (n = 119) A1 A2 (n = 471) A1 R1 (n = 915) Odds ratio E1 + A1 vs A2 or R1 2.51** 1.77* 9.46** 3.9** B 1 LDL-C <1 mg/dl LDL-C <7 mg/dl % patients attaining specified LDL-C target LDL-C 1 to 16 mg/dl on: A2 A2 Treatment period II E1 + A2 A4 (n = 12) (n = 123) R1 R1 E1 + A2 R2 (n = 228) (n = 21) A2 A2 E1 + A2 A4 (n = 12) (n = 123) R1 R1 E1 + A2 R2 (n = 228) (n = 21) Odds ratio E1 + A2 vs A4 or R2 2.71** 2.38** 27.77* 7.8** Figure 2. Percentage attainment of prespecified LDL-cholesterol targets in two-period study evaluating combination ezetimibe+atorvastatin versus atorvastatin uptitration or switching to rosuvastatin therapy.(a) Percentage attainment of prespecified LDL-C target after 6 weeks (period I). (B) Percentage attainment of prespecified LDL-C target after 6 weeks (period II). Ratio of the predictive odds of achieving LDL-C level on E1 + A1 versus either A2 or R1. Ratio of the predictive odds of achieving LDL-C level on E1 + A2 versus either A4 or R2. * p <.1 ** p <.1 A1: Atorvastatin 1 mg/day; A2: Atorvastatin 2 mg/day; E1: Ezetimibe 1 mg/day; R1: Rosuvastatin 1 mg/day; R2: Rosuvastatin 2 mg/day. Adapted with permission from [61]. 452 Clin. Lipidol. (214) 9(4) future science group

14 Efficacy & safety of ezetimibe plus atorvastatin therapy Review procedure by 17% compared with placebo during a median follow-up period of 4.9 years (relative risk [RR]:.83; 95% CI:.74.9; p =.2). Patients in the study had an average 2/3 adherence rate, and an absolute difference in LDL-C reduction of 33 mg/ dl. While the study was not powered to demonstrate significant reductions for the individual components of the MAE end point, significant reductions in nonhemorrhagic stroke (RR:.75; 95% CI:.6.94; p =.1) and revascularization procedures (RR:.79; 95% CI:.68.93; p =.36) were observed as well as numerically fewer major coronary events (RR:.92; 95% CI: ; p =.37) which reflected nonsignificantly fewer nonfatal MIs (RR:.84; 95% CI: ; p =.12) and no significant difference in CHD death (RR: 1.1; 95% CI: ; p =.95). Major vascular events (MAE + noncoronary cardiac deaths + hemorrhagic stroke) were also reduced by 15% with the combination compared with placebo (RR:.85; 95% CI:.77.94; p =.12). The overall observed reduction of cardiovascular events was per mmol LDL-C lowering (39 mg/dl), was consistent with results from the Cholesterol Treatment Trialists (CTT) meta-analysis of statin t rials in patients w ithout CKD [1,2]. Although the study was not powered to assess MAE in patient subgroups, the treatment effects were generally consistent among all subgroups evaluated, including dialysis and nondialysis patients (test for heterogeneity between groups p =.25). The difference in the proportional treatment effects was not statistically significant between these two patient groups; however, the treatment effect on MAE appeared to be somewhat attenuated in patients on dialysis at baseline (RR:.9; 95% CI: ) compared with those not on dialysis (RR:.78; 95% CI:.67.91). This was likely due to lower mean baseline LDL-C levels and reduced treatment compliance among patients on dialysis at baseline, resulting in smaller absolute LDL-C reductions (23 mg/dl) compared with the nondialysis cohort patients (31 mg/dl). After weighting the LDL-C reductions, the proportional reductions of MAE per 1 mmol/l (38.6 mg/dl) LDL-C reduction were similar (16 25%) across stages 3 5 CKD patients, and those patients on dialysis at baseline. Among the patients who were not on dialysis at baseline, combination ezetimibe plus simvastatin did not have a significant effect on any of the prespecified measures of renal disease progression (progression to end-stage renal disease [ESRD], ESRD plus time to doubling of serum creatinine, ESRD or death), although findings for all of these measures were directionally favorable. It should be noted that some studies in patients with less-advanced renal disease have shown slowing of loss of renal function with statin treatment over time [171,172]. Taken together, the SHARP study results demonstrated that cholesterol-lowering therapy, and specifically ezetimibe 1 mg plus simvastatin 2 mg, reduced atherosclerosisrelated vascular events in moderate-to-advanced CKD patients. To date, SHARP is the only study that has shown a benefit of lipid-lowering therapy on cardiovascular outcomes in patients with advanced CKD and the study results have been published in guidelines on cholesterol management as supporting evidence/information for recommendations regarding treatment of CKD patients [6,9,81]. In prior statin trials in CKD dialysis patients, the absence of significant reductions of CVD events may be attributed to smaller study populations and to lower proportions of atherosclerotic-related events specified in the primary outcome end point in these trials than would be expected to be modifiable by lowering of LDL-C levels [99, ]. Additionally, because dialysis patients commonly have lower LDL-C levels at baseline, CVD risk reduction, which is proportional to absolute change in LDL-C, is correspondingly smaller [1,19,55]. Studies of larger populations, including post hoc analyses of statin trials in patients with stages 2 3 CKD, and meta-analyses of statin trials have shown a benefit of LDL-C lowering on a reduction in recurrent CVD events in patients at all stages of CKD, as well as a reduction in all-cause and CVD mortality in those who were not on d ialysis [ ]. SEAS The effect of ezetimibe 1 mg plus simvastatin 4 mg versus placebo on a composite of major aortic-valverelated events (AVE) and ischemic cardiovascular events (ICE) was studied in 1873 patients with mildto-moderate aortic stenosis (AS) and no history of prior CHD in the SEAS trial [56]. The observed rates of any major cardiovascular event (AVE plus ICE), were not significantly different in the ezetimibe plus simvastatin (35.3%) and placebo (38.2%) groups, despite a 5% reduction in LDL-C levels compared with placebo. The end point category of aortic valve replacement comprised the large majority of primary end point events. There was also no significant difference in the end point of AVE alone, (comprised of aortic valve replacement, death from cardiovascular causes and hospitalization for heart failure) with either treatment. However, the ICE composite end point (cardiovascular death, nonfatal acute myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, hospitalization for unstable angina pectoris, nonhemorrhagic stroke) was future science group 453

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